The present invention relates to an aqueous suspension with good redispersibility.
In preparing, for instance, an ophthalmic preparation, nasal preparation or parenteral preparation containing a medicinal compound hardly soluble in water, it is presumable that the drug be suspended in an aqueous medium to give an aqueous suspension. When such aqueous suspension is stored for a long period, the drug occurring as dispersed particles (hereinafter sometimes referred to merely as dispersed particles) tends to undergo aggregation, resulting in increases in size of dispersed particles or sedimentation of dispersed particles and further in secondary aggregation of the dispersed particles that have settled, for example caking. Therefore, efforts have been devoted to prevent the aggregation or sedimentation of dispersed particles as far as possible or, when such aggregation or sedimentation cannot be prevented, to obtain suspensions capable of readily regaining their original state.
One method so far proposed comprises making dispersed particles smaller, decreasing the difference between the specific gravity of dispersed particles with of the dispersion medium and increasing the viscosity of the dispersion medium to thereby prevent the particles from settling. In such cases, for increasing the viscosity of the dispersion medium, the concentration of the suspending agent and/or thickening agent, such as a water-soluble polymer, has generally been selected within the range of 0.2 to 5.0% (w/v: weight/volume).
However, even when the concentration of the suspending agent and/or thickening agent is within such range, the sedimentation of particles cannot entirely be prevented. The problem which remains is that dispersed particles settle and deposit, causing caking, resulting in failure of uniform redispersion.
Another method which is conceivable comprises making drug particles greater in size to thereby improve their redispersibility. In the case of an ophthalmic preparation, however, greater particle sizes may cause a foreign matter sensation or eye irritation upon instillation. In the case of a nasal preparation, greater particle sizes make it impossible to apply it from a spray bottle. In the case of an injection, it is a drawback that it cannot be administered through a needle.
Among the drugs recently developed and producing pharmacological effects of value, many are hardly soluble ones. For supplying these in the form of aqueous preparations such as ophthalmic, nasal, parenteral and other preparations, it is unavoidable in many instances to employ the aqueous suspension form. However, the prior art aqueous suspensions have a redispersibility problem; in many instances, it is difficult to restore suspensions uniform in concentration without a long time of shaking to effect redispersion. Thus, the advent of aqueous drug suspensions which can be readily prepared and have good redispersibility has been waited for. Accordingly, it is the primary object of the present invention to provide an aqueous suspension showing good redispersibility without undergoing aggregation of dispersed particles or caking.
The present inventors made intensive investigations to solve the above problems and, as a result, found that there is a certain relationship between the surface tension of an aqueous suspension and the redispersibility thereof. Based on such finding, they have now completed the present invention.
The invention is thus concerned with an aqueous suspension comprising a hardly soluble drug together with a water-soluble polymer within the concentration range from the concentration at which the surface tension of the drug suspension begins to decrease up to the concentration at which the reduction in surface tension ceases.
As will be shown later herein in Test Example 1, the surface tension of an aqueous suspension begins to decrease with the increase in the amount of a water-soluble polymer added thereto. Upon continuation of the addition, the reduction in surface tension ceases and, thereafter, a substantially constant surface tension is maintained. On the contrary, the redispersibility of the dispersed particles of an aqueous suspension becomes good at the point at which the surface tension of the aqueous suspension begins to decrease as a result of addition of the water-soluble polymer, and the good redispersibility is maintained until the reduction in surface tension ceases. Thereafter, as the reduction in surface tension ceases and the surface tension becomes constant, the redispersibility of the dispersed particles becomes gradually worsened.
Where no water-soluble polymer is present, the dispersed particles aggregate together and float on the surface of the suspension and therefore no uniform suspension can be prepared.
The concentration of a water-soluble polymer at which the surface tension of an aqueous drug suspension begins to decrease and the concentration of the water-soluble polymer at which the reduction in surface tension ceases generally increase according to the contents of the hardly soluble drug used in the aqueous suspension but vary depending on the physical properties, chemical structure, and concentration and particle size of the hardly soluble drug, among others. The water-soluble polymer concentration at which the surface tension of the drug suspension begins to decrease is generally 0.00001 to 0.01% (w/v), preferably 0.00005 to 0.005% (w/v), while the water-soluble polymer concentration at which the reduction in surface tension of the suspension ceases is generally 0.0001 to 0.1% (w/v), preferably 0.001 to 0.01% (w/v).
The aqueous suspension of the present invention is generally prepared at a water-soluble polymer concentration within the range of 0.00001 to 0.1% (w/v), preferably 0.00005 to 0.05% (w/v), more preferably 0.0001 to 0.01 w/v %.
The ratio of the water-soluble polymer to the hardly soluble drug is generally 0.0001 to 0.2 part by weight, preferably 0.0005 to 0.1 part by weight, more preferably 0.0005 to 0.05 part by weight of the former to 1 part by weight of the latter.
The water-soluble polymer to be used in the practice of the present invention may be any pharmaceutically acceptable water-soluble polymer, irrespective of type or category. Cellulose derivatives and water-soluble polyvinyl polymers are suited for use, however.
As the cellulose derivatives, there may be mentioned, for example, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose and hydroxypropylcellulose. Particularly preferred among them are hydroxypropylmethylcellulose and methylcellulose.
As the water-soluble polyvinyl polymers, there may be mentioned, among others, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, and polyvinyl alcohol (partial hydrolyzed product, complete hydrolyzed product).
As used herein, the xe2x80x9chardly soluble drugxe2x80x9d includes, within the meaning thereof, those drugs which belong, in solubility classification, to one of the groups xe2x80x9csparingly solublexe2x80x9d, xe2x80x9cslightly solublexe2x80x9d, xe2x80x9cvery slightly solublexe2x80x9d and xe2x80x9cpractically insolublexe2x80x9d as so defined in the Japanese Pharmacopoeia. Thus, it includes all drugs that can be provided in the final dosage form of aqueous suspensions.
As specific examples of the hardly soluble drug to be used in the practice of the present invention, there may be mentioned steroidal antiinflammatory agents, antiinflammatory analgesics, chemotherapeutic agents, synthetic antibacterial agents, antiviral agents, hormones, anticataract agents, neovascularization inhibitors, immunosuppressants, protease inhibitors, and aldose reductase inhibitors, among others. The steroidal antiinflammatory agents include, among others, cortisone acetate, hydrocortisone acetate, betamethasone, prednisolone, fluticasone propionate, dexamethasone, triamcinolone, loteprednol, fluorometholone, difluprednate, momethasone furoate, clobetasol propionate, diflorasone diacetate, diflucortolone valerate, fluocinonide, amcinonide, halcinonide, fluocinolone acetonide, triamcinolone acetonide, flumetasone pivalate and clobetasone butyrate. The antiinflammatory analgesics include, among others, alclofenac, aluminopropfen, ibuprofen, indomethacin, epirizole, oxaprozin, ketoprofen, diclofenac sodium, diflunisal, naproxen, piroxicam, fenbufen, flufenamic acid, flurbiprofen, floctafenine, pentazocine, metiazinic acid, mefenamic acid and mofezolac. The chemotherapeutic agents include, among others, sulfa drugs such as salazusulfapyridine, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfamethopyrazine and sulfamonomethoxine, synthetic antibacterial agents such as enoxacin, ofloxacin, cinoxacin, sparfloxacin, thiamphenicol, nalidixic acid, tosufloxacin tosilate, norfloxacin, pipemidic acid trihydrate, piromidic acid, fleroxacin and levofloxacin, antiviral agents such as aciclovir, ganciclovir, didanosine, didovudine and vidarabine, and antifungal agents such as itraconazole, ketoconazole, fluconazole, flucytosine, miconazole and pimaricin. The hormones include, among others, insulin zinc, testosterone propionate and estradiol benzoate. The anticataract agents include, among others, pirenoxine and the like. The neovascularization inhibitors include, among others, fumagillin and derivatives thereof. The immunosuppressants include, among others, ciclosporin, rapamycin and tacrolimus. The protease inhibitors include, among others, [L-3-trans-ethoxycarbonyloxiran-2-carbonyl]-L-leucine (3-methylbutyl)amide (E-64-d) and the like. The aldose reductase inhibitors include, among others, 5-(3-ethoxy-4-pentyloxyphenyl)thiazolidine-2,4-dione and the like.
The concentration of the hardly soluble drug to be used in the practice of the invention may vary according to the drug species, indication, dosage and other factors. Generally, however, it is 0.01 to 10.0% (w/v), preferably 0.1 to 5.0% (w/v).
The aqueous suspension of the present invention may contain, in addition to the hardly soluble drug and water-soluble polymer, known compounds such as a buffer (e.g. carbonate salt, phosphate salt, acetate salt, glutamic acid, citrate salt, xcex5-aminocaproic acid), an isotonizing agent (e.g. glycerol, mannitol, sorbitol, propylene glycol, sodium chloride, potassium chloride, boric acid), a stabilizer (e.g. sodium edetate, sodium citrate), a surfactant (e.g. polysorbate 80, polyoxyethylene(60) hydrogenated castor oil, tyloxapol, benzalkonium chloride), a preservative (p-hydroxybenzoate and it""s analogs, benzalkonium chloride, benzethonium chloride, chlorobutanol), a pH control agent (e.g. hydrochloric acid, sodium hydroxide, phosphoric acid), and other additives.
In cases where an additive which may influence the surface tension of the aqueous suspension, for example a surfactant, is used, it is preferred that the surface tension measurement be made prior to addition of the surfactant and the surfactant be added after selection of the concentration of the water-soluble polymer.
The pH of the aqueous suspension of the present invention is not critical but, generally, it is 4 to 9, preferably 5 to 8. It is preferred that the surface tension be selected according to the intended pH of the aqueous suspension.
The aqueous suspension of the invention has good redispersibility without involving aggregation or caking of dispersed particles and, therefore, can be used with advantage as, for example, an ophthalmic preparation, a preparation for nasal application, an injection, a preparation for oral administration or a lotion.